Decrease in Venous Irritation by Adjusting the Concentration of Injected Bendamustine

Abstract

Intravenous injection of bendamustine often causes venous irritation and also deteriorates the patient’s quality of life. Thus, we evaluated the risk factors associated with venous irritation induced by bendamustine in patients with follicular lymphoma or mantle cell lymphoma. We also evaluated the effectiveness of intervention of changing the preparation procedure for bendamustine. All data were retrospectively collected from the electronic medical record system. In the initial analysis of the total 43 courses of bendamustine therapy, most patients (88%) were administered bendamustine with 250 mL of diluent according to the bendamustine package insert in Japan. The median concentration of bendamustine solution (0.56 mg/mL vs. 0.24 mg/mL) and the incidences of venous irritation (66% vs. 0%, p=0.01) were significantly different between the patients receiving bendamustine at 250 mL and 500 mL of diluent. Based on this result, we proposed changing the final volume of bendamustine dissolution from 250 to 500 mL, which is recommended in other countries. After this intervention, the incidence of venous irritation was significantly reduced from 58 to 20% (p=0.02). The incidence of venous irritation increased in a concentration-dependent manner (≤0.40 mg/mL: 6%; 0.41–0.60 mg/mL: 62%, p<0.001; >0.60 mg/mL: 75%, p<0.001). We conclude that a high concentration bendamustine solution is a risk factor for venous irritation and that 500 mL of diluent is ideal. To further reduce the incidence of venous irritation, the concentration of bendamustine solution is recommended to be 0.40 mg/mL or less.

Bendamustine, originally designed to have both alkylating¹⁾ and antimetabolite properties,²⁾ has shown clinical activity against various human malignancies including non-Hodgkin’s lymphoma^3–7) and chronic lymphocytic leukemia.⁸⁾ According to the National Comprehensive Cancer Network (NCCN) guidelines for patients with non-Hodgkin’s lymphoma,⁹⁾ bendamustine alone or bendamustine with rituximab is used for patients with follicular lymphoma or mantle cell lymphoma. However, intravenous injection of bendamustine often causes venous irritation such as erythema, injection site pain and phlebitis.¹⁰⁾ Venous irritation often limits the continuation of chemotherapy and also deteriorates the patient’s quality of life.

Bendamustine is marketed as TREAKISYM Injection® in Japan and TREANDA Injection® in the U.S. The incidences of bendamustine-induced venous irritation at approval were 30.8% in Japan¹¹⁾ but less than 10% in the U.S.¹²⁾ In the TREAKISYM Injection® package insert,¹¹⁾ it indicates that the final volume of bendamustine should be set at 250 mL. On the other hand, the TREANDA Injection® package insert¹²⁾ recommends 500 mL as the final volume of bendamustine and 0.2–0.6 mg/mL as the concentration. This difference may be important in the occurrence of venous irritation. However, the correlation between the final volume and concentration of bendamustine diluent and the incidence of venous irritation has not been clarified.

In Kyushu University Hospital, venous irritation is frequently caused when bendamustine is administered according to the procedure described in the package insert of TREAKISYM Injection®. To prevent venous irritation, some physicians have tried to dissolve bendamustine in 500 mL of normal saline, mix dexamethasone into the bendamustine solution or administer bendamustine through a Y-site of the main infusion route of a hydration bag. However, the effectiveness of these attempts has not been fully elucidated. In the present study, we analysed the risk factors associated with venous irritation in patients treated with bendamustine. Then, we changed the bendamustine preparation procedure and evaluated the effectiveness of the intervention.

Materials and Methods

Patients

The present study was conducted in accordance with the Declaration of Helsinki and its amendments, and the protocol was approved by the Ethics Committee of Kyushu University Graduate School and Faculty of Medicine (approval No. 23-113 of the institutional review board). The subjects in the present study were 21 patients who received totally 58 courses of bendamustine or R-B (rituximab and bendamustine) chemotherapy from December 2010 to November 2011.

Study Protocol and Intervention

Initially, bendamustine (120 mg/m² for bendamustine alone therapy and 90 mg/m² for R-B therapy) was administered intravenously in a final volume of 250 mL of normal saline over 60 min on days 1 and 2. Rituximab 375 mg/m² was administered on day 0.

All data were collected from the nursing records and the electronic medical charts. Venous irritation was retrospectively assessed by the existence or non-existence of infusion site pain, swelling and redness using the medical record system. Univariate analysis was conducted to determine factors associated with venous irritation.

Based on the initial results of 43 courses, we proposed changing the preparation procedure for bendamustine to that used in the U.S. (dilution in the final volume of 500 mL) to the Cancer Chemotherapy Review Committee. The infusion time of bendamustine was extended from 60 to 120 min. After changing the procedure in principle (intervention), the data of 15 courses were collected. Then, we evaluated the effectiveness of changing the procedure, and examined the risk factors for the incidence of venous irritation.

Statistical Analyses

Data were analyzed by the Mann–Whitney U test (age, body mass index and dose of bendamustine), Fisher’s exact test (gender, protocol of chemotherapy, volume of diluted solution, concentration of bendamustine and addition of dexamethasone to the bendamustine solution) or Chi-square test (course of bendamustine treatment and number of prior chemotherapies). The Mann–Whitney U test was performed to compare the concentration of the bendamustine solution between the differences of bendamustine diluents. In cases in whom bendamustine solution was administered through a Y-site of the main infusion solution for hydration, the final concentration of bendamustine was calculated from the flow rates of both the bendamustine solution and hydration fluid. To identify the risk factors associated with bendamustine-induced venous irritation, univariate analysis was conducted. The difference in frequency of venous irritation was analyzed by Fisher’s exact test. Data were analyzed using JMP8.0.0.2 (SAS Institute Inc., Cary, NC, U.S.A.), and p values of <0.05 were considered statistically significant.

Results

The characteristics of patients with or without bendamustine-induced venous irritation are shown in Table 1. Before the intervention, bendamustine was administered in 250 mL or 500 mL of diluent in 38 (88%) and 5 (12%) of 43 courses, respectively. Venous irritation was observed in 66% (25 of 38) of courses when bendamustine was administered in 250 mL diluent, but not in 500 mL diluent (0 of 5) (p=0.009). The median concentration of bendamustine solution was 0.56 mg/mL (range, 0.45–0.72 mg/mL) when it was diluted in 250 mL of saline, but it was 0.24 mg/mL (range, 0.24–0.36 mg/mL) when diluted in 500 mL of saline (p<0.001).

Table 1. Characteristics of Patients with or without Venous Irritation

Venous irritation	Before intervention			After intervention		Total
	(+) N=25	(−) N=18	p value	(+) N=3	(−) N=12	(+) N=28	(−) N=30	p value
Age (year)
Median (range)	57 (49–77)	58 (49–76)	0.164	77 (51–77)	56 (51–77)	58 (49–77)	58 (49–77)	0.372
Gender
Male	18	15	0.480	1	9	19	24	0.373
Female	7	3		2	3	9	6
Body mass index (kg/m2)
Median (range)	23.6 (17.2–25.4)	21.8 (17.2–25.4)	0.990	20.3 (20.3–20.5)	20.6 (17.2–25.1)	22.0 (17.2–25.4)	21.8 (17.2–25.4)	0.708
Number of prior chemotherapies
1	14	11	0.800	0	5	14	16	0.898
2	6	5		0	0	6	5
3 or more	5	2		3	7	8	9
Therapy
R-Ba)	21	16	1.000	1	9	22	25	0.744
Bendamustine	4	2		2	3	6	5
Dose of bendamustine (mg)
Median (range)	153 (120–180)	150 (135–180)	0.191	120 (120–160)	153 (120–165)	153 (120–180)	150 (120–180)	0.427
Volume of diluted solution
250 mL	25	13	0.009	2	1	27	14	<0.001
500 mL	0	5		1	11	1	16
Concentration of bendamustine (mg/mL)b)
0–0.40	0	5	—	1	11	1	16	<0.001
0.41–0.60	16	10		2	1	18	11
>0.60	9	3		0	0	9	3
Administration through a Y-site injection route
(+)	10	5	0.407	0	1	10	6	0.243
(−)	15	13		3	11	18	24
Dexamethasone
(+)	5	1	0.375	0	1	5	2	0.264
(−)	20	17		3	11	23	28

a) R-B=rituximab+bendamustine. b) Cases in whom bendamustine solution was administered through a Y-site of the main infusion solution for hydration, the final concentration of bendamustine was calculated from the flow rates of both the bendamustine solution and hydration fluid.

After intervention in which the final volume of the bendamustine diluent was changed from 250 to 500 mL, such volumes were used in 3 (20%) and 12 (80%) of 15 courses. When 250 mL was used, venous irritation was observed in 2 (67%) of 3 courses. When 500 mL was used, it was observed in 1 (8%) of 12 courses.

Among the patients both before and after intervention, the median concentration of bendamustine was 0.56 mg/mL (range, 0.44–0.72 mg/mL) when it was diluted in 250 mL of saline, but it was 0.31 mg/mL (range, 0.20–0.36 mg/mL) when diluted in 500 mL of saline (p<0.001). Following the intervention, the percentage of 250 mL bendamustine dilution use was significantly decreased from 88 to 20% (p<0.001), and the incidence of venous irritation was significantly decreased from 58 to 20% (p=0.016) (Fig. 1A).

Fig. 1. The Relationships between Incidence of Venous Irritation before and after Intervention (A), Volumes of Diluted Solutions (B) or Concentrations of Bendamustine (C)

In all the courses examined, the frequency of venous irritation was significantly lower when bendamustine diluent used was 500 mL rather than 250 mL (6% vs. 66%, p<0.001) (Fig. 1B). The incidences of venous irritation were 6% (1/17), 62% (18/29) and 75% (9/12) when the concentrations of bendamustine were low (≤0.40 mg/mL), medium (0.41–0.60 mg/mL) and high (>0.60 mg/mL), respectively (Fig. 1C).

Discussion

In this study, we examined the risk factors for bendamustine-induced venous irritation. Because a significant relationship was observed between the volume of bendamustine diluent and the incidence of venous irritation, we changed the volume of bendamustine solution from 250 to 500 mL (intervention). After the intervention, the frequency of venous irritation was significantly reduced. Moreover, the incidence of bendamustine-induced venous irritation was observed in a concentration-dependent manner. These results revealed that the concentration of bendamustine is an important risk factor for venous irritation.

After the intervention, the ratio of patients receiving bendamustine in 250 mL of diluent decreased from 88 to 20%. As a result, the incidence of venous irritation significantly decreased from 58 to 20%. Although it is recommended to dilute bendamustine in 250 mL of normal saline in Japan,¹¹⁾ it is recommended to be administered after adjusting the final liquid volume to 500 mL or a final concentration of 0.2–0.6 mg/mL in the U.S.^12,13) and other countries.¹⁴⁾ In the present study, the median concentration of bendamustine was 0.31 mg/mL when it was diluted in 500 mL of saline, but it was 0.56 mg/mL when diluted in 250 mL of saline. Nakashima et al.¹⁵⁾ reported that co-administration of 5% glucose solution 250 mL and bendamustine solution dissolved in 250 mL of saline reduced vascular pain grade in 3 patients with folicular lymphoma. Totally, 500 mL of bendamustine solution was used in these cases.

No literature showed high concentration of bendamustine is an important risk factor for venous irritation. This is the first report which showing that the incidence of bendamustine-induced venous irritation increased in a concentration-dependent manner (Fig. 1C). For example, in a patient with 2.0 m² of body surface area (BSA) receiving bendamustine at 120 mg/m², the calculated concentration is 0.48 mg/mL. Therefore, even if bendamustine is dissolved in 500 mL, there may be a risk of venous irritation in some patients.

Although the mechanism of the onset of venous irritation remains unclear, we reported that vinorelbine, which also often causes vascular injury, induced cell injury in vascular endothelial cells dose-dependently.¹⁶⁾ It is possible that the damage to vascular endothelial cells is also involved in bendamustine-induced venous irritation. In addition to the stimulus properties of the drug, the osmotic pressure and the pH (a range between 5 and 9 is advisable) of the infused solution are associated with drug-induced venous toxicity.¹⁷⁾ However, since the osmotic pressure ratio of saline-diluted bendamustine solution (0.4 mg/mL) to normal saline is about 0.9,¹¹⁾ it is unlikely to be a factor in venous irritation. The pH of saline-diluted bendamustine solution is relatively low (0.4 mg/mL; pH=3.69), but an increase in volume of bendamustine dissolution has only a slight effect on the pH (0.32 mg/mL: pH=3.76; 1.2 mg/mL: pH=3.41).¹¹⁾ Therefore, the pH is not likely to be involved in bendamustine-induced venous irritation.

Kohno et al.¹⁸⁾ reported the protective effect of corticosteroids on phlebitis induced by anticancer drugs in rabbit model. A part of the mechanisms of bendamustine-induced venous irritation can be explained by irritation of vascular endothelial cells. In this study, however, venous irritation occurred in 5 of 7 patients who received bendamustine solution mixed with dexamethasone, suggesting that dexamethasone is insufficient for preventing bendamustine-induced venous irritation.

Limitations of this study include lack of investigation of mechanism of the onset of venous irritation. We could not perform multivariate analysis to reveal factors associated with bendamustine-induced venous irritation, because of the low number of patients in this study. Therefore, there may be other risk factors other than the concentration of bendamustine. In addition, no evaluation of clinical effect of bendamustine was evaluated when we changed the regimen. When the volume of the bendamustine diluent was increased from 250 to 500 mL in this study, the infusion time was extended from 60 to 120 min. Bendamustine is generally infused intravenously over 30–60 min.^11–14) In a randomized control trial for patients with indolent B-cell non-Hodgkin’s lymphoma, bendamustine at a concentration of 120 mg/m² was infused over 60–120 min and no changes in the effectiveness or safety of bendamustine were observed. Therefore, prolongation of the infusion time from 60 to 120 min may be appropriate, although it is unclear whether the prolongation affects the incidence of venous irritation. In general, the incidence of venous irritation is decreased when anticancer drugs administered for a short time. Although we do not have those data, the incidence of venous irritation might be lower if the infusion rate would be increased 2-fold with half-concentration of bendamustine. Further studies will be necessary to confirm this hypothesis.

In conclusion, a high concentration of bendamustine was a strong risk factor in the incidence of venous irritation. Based on our results, we altered the volume of normal saline for bendamustine dissolution from 250 to 500 mL. This intervention significantly decreased the risk of bendamustine-induced venous irritation. To further reduce the incidence of venous irritation, the concentration of bendamustine solution is recommended to be set at 0.40 mg/mL or less.

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